New Insights Into How Certain Slow Progressers Control HIV Infection
People with a rare genetic trait who are infected with HIV progress more slowly to AIDS than others. But even within this group, there are wide variations in time to progression. A new study illustrates in detail how the immune system fights the virus in those subjects who progress more slowly. The research, which could prove useful to efforts to develop a vaccine against HIV, is published in the September Journal of Virology.
Absent antiretroviral therapy, most of those infected with HIV progress to AIDS within a decade. But 5-15 percent remain symptom free for years even without therapy. A portion of these people maintain high CD4+T immune cell counts, along with low levels of virus for several years. Many of these people possess the afore-mentioned rare genetic trait, the awkwardly-named HLA-B*5701 allele (an allele is one possible version of a gene), and their time of progression can range from around six years to well beyond ten years.
The researchers, led by Melissa M. Norstrom and Annika K. Karlsson of the Karolinska Institute, Stockholm, Sweden, and Marco Salemi of the University of Florida, Gainesville, studied evolution of HIV, and immune responses in six untreated HIV-infected patients carrying the protective genetic trait, following them from soon after infection, for seven years. In particular, they studied a set of molecules that are produced by immune cells called CD8+T cells, which are involved in combating viral infections.
“We found that subjects with lower risk of progressing to AIDS were characterized by a higher proportion of CD8+T cells that produced several of these molecules simultaneously,” says Norstrom. They also found that in these patients, the virus evolved much more slowly. Further, viral mutations, which normally occur somewhat haphazardly during HIV infection, appeared to happen in a specific order, which the researchers postulate resulted from selective constraints exerted by the immune system.
“Understanding the mechanisms associated with slower progression to AIDS may ultimately provide new insights on how to cure HIV, or even how to develop a protective vaccine,” says Salemi.
The research had a serendipitous origin, when Norstrom and Salemi met at a workshop on viral evolution, says Salemi. “The exciting discussions during that scientific meeting led to establishment of a successful multidisciplinary collaboration, which included experts in immunology and viral evolution, as well as with Dr. [Frederick M.] Hecht at the University of California, San Francisco, who provided samples from patients carrying this unique genetic trait.”
(M.M. Norstrom, M. Buggert, J. Tauriainen, W. Hartogensis, M.C. Prosperi, M.A. Wallet, F.M. Hecht, M. Salemi, and A.C. Karlsson, 2012. Combination of immune and viral factors distinguishes low-risk versus high-risk HIV-1 disease progression in HLA-B*5701 Subjects. J. Virol. 86:9802-9816.)
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Researchers Map Molecular Details That Encourage H1N1 Transmission To Humans
The 2009 H1N1 pandemic influenza virus appears to have required certain mutations in order to be transmitted to humans, according to a paper in the September Journal of Virology.. The research could prove extremely valuable for efforts to predict human outbreaks.
The 2009 influenza pandemic was caused by a swine influenza virus that mutated in a way that made it transmissible among humans. The researchers, led by Hualan Chen of the Harbin Veterinary Research Institute, Harbin, China, have determined the probable details of the mutations that led to human transmission.
In this study, Chen, who is director of the National Avian Influenza Reference Laboratory at the Institute, and her collaborators have shown that two specific mutations in each of two proteins appear to be critical to transmission to, and among humans. One of those mutations, of a single amino acid in the virus’ hemagglutinin protein, gives the virus the ability to bind to human receptors, and enables transmission in mammals via droplets of respiratory fluids.
That amino acid, in the 226th slot in the protein, is glutamine. The researchers showed its importance by causing a mutation from glutamine, the amino acid in that position seen in viruses from infected humans, to argenine, as seen in swine. Working in cell cultures, the researchers showed that the switch dampened the virus’ ability to bind the human receptor, while boosting its ability to bind to the avian receptor. They showed further that the change rendered the virus non-transmissible via respiratory droplets in guinea pig models, and unable to replicate in the lungs of ferrets – results that suggest, but do not prove that the same may happen in humans.
Also in guinea pigs, changing an amino acid in the virus’ PB2 protein abolished transmission in guinea pigs via respiratory droplets, while that change, plus another single amino acid change in the hemagglutinin protein, killed such transmission in ferrets.
It gets still more convoluted. The same amino acid in the PB2 protein that enables virus transmission via respiratory droplets, which is located at position 271 in that protein, can also encourage the afore-mentioned mutation in hemagglutinin position 226 to glutamine, which enables the virus to cleave to the human receptor.
The value of all this information, says Chen, is that it provides a means for predicting outbreaks of human-transmissible H1N1.
(Y. Zhang, Q. Zhang, Y. Gao, X. He, H. Kong, Y. Jiang, Y. Guan, X. Xia, Y. Shu, Y. Kawaoka, Z. Bu, and H. Chen, 2012. Key molecular factors in hemagglutinin and PB2 contribute to efficient transmission of the 2009 H1N1 pandemic influenza virus. J. Virol. 86:9666-9674.)
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Probiotics to Decontaminate Your Gut?
Heavy metals and other toxins frequently contaminate food and water. The culprits read like a litany of bad actors – lead, cadmium, mercury, arsenic, chromium – but their numbers run into the thousands. Microbes have long been enlisted for bioremediation, but they also have the potential to protect us from toxins, according to a minireview in the September Applied and Environmental Microbiology. “Beneficial bacteria are indeed capable of degrading pesticides and sequestering toxic chemicals,” says coauthor Gregor Reid of the Lawson Health Research Institute, London, Ontario.
Indeed, 40 to 60 percent of metals ingested by humans into the gastrointestinal (GI) tract do not breach the intestinal barrier, and host microbiota play an important role in preventing their entry, says coauthor Jeremy Burton, of Lawson. Lactobacilli are prominent denizens of the GI and vaginal tract, and are also frequently used in fermentation, says Burton. That raises the possibility of applying them to other foods to sweep harmful compounds from the gut, and even decontaminating environmental sites. “If the metal is trapped in or on a bacterial cell, it can pass harmlessly from the body via feces,” he explains.
The concept grew out of Reid’s group’s interest in how lactobacilli can improve urogenital health in women. “We realized that lives could be improved by the relatively simple approach of using probiotics that pass through the gut and ascend to the vagina,” says Reid. That led to development of several probiotic yogurts, one of which was transferred to local community kitchens in Tanzania, Kenya, and Rwanda, where it has been shown to help people infected with HIV who were malnourished and suffering from diarrhea.
“As large parts of the world, including Africa’s Lake Victoria [the world's second largest freshwater lake by surface area], are contaminated by a host of toxic compounds, we thought it would be worth seeing if lactobacilli could counter the toxins,” says Reid.
The researchers hope their minireview will spur discussion of these ideas, and further experimentation. “We are testing this theory in several studies, and would welcome collaborations to explore just how much of a detox effect can be achieved through microbes and food,” says Burton.
(M. Monachese, J.P. Burton, and G. Reid, 2012. Bioremediation and tolerance of humans to heavy metals through microbial processes: a potential role for probiotics. Appl. Environ. Microbiol. 78:6397-6404.)
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Wild Boars Are Reservoir of Hepatitis E Virus: High Prevalence Among Forestry Workers in Eastern France
Nearly one third of forestry workers in parts of eastern France are infected with Hepatitis E virus (HEV), according to a paper in the September Journal of Clinical Microbiology. Wild boars in the same region are also heavily infected. HEV is endemic in developing nations, but heretofore, HEV infection in industrialized nations has been most closely correlated with travel to developing nations.
The prevalence of HEV was found to be 14 percent among wild boar, about half that in pigs, says principal investigator Pierre Coursaget of the University of Tours, France. An earlier study found 12 percent prevalence among boar in The Netherlands. Among humans in the current study, the prevalence of anti-HEV antibodies increases with age, and varies with occupation and geographic location within eastern France. “The frequency of HEV infections in humans did not correlate with the number of pigs, locally, but there is good correlation with the number of car accidents due to wild boars,” a surrogate for contact between humans and wild boars, says Coursaget.
HEV is transmitted orally and fecally, with mortality rates of 1-3 percent in the general population, rising to 20-25 percent among pregnant women. In developing countries, outbreaks appear to arise from fecally contaminated water supplies. In Japan, and in Europe, consumption of wild boar or liver is associated with a high risk of acquiring hepatitis E virus infection, according to the report. However, the fact that HEV is absent among children in France suggests that eating ham is safe. Coursaget says the immune system in healthy people generally eradicates the infection, and that it is not sexually transmitted.
Deer also are known to be infected with HEV, says Coursaget. “People in contact with HEV-infected animals or their environment must be aware of the possibility of HEV infection,” he says. He is currently studying HEV infection in forestry workers, veterinarians, and pig farmers in different regions of France, in an effort to quantify risk factors. The current study also compared several antibody tests for HEV, with one, the HEV ELISA test, from MP Biologicals, proving superior to the other two.
(A. Carpentier, H. Chaussade, E. Rigaud, J. Rodriguez, C. Berthault, F. Boue, M. Tognon, A. Touze, N. Garcia-Bonnet, P. Choutet, and P. Coursaget, 2012. High hepatitis E virus seroprevalence in forestry workers and wild boars in France. J. Clin Microbiol. 50:2888-2893.)